The overall objective of this proposal is to provide information which will aid in the identification of conditions in which individuals might be unusually susceptible (or resistant) to the toxic actions of pesticides. The project will focus on the organophosphorus insecticides since they represent the major class of chemicals used as insecticides, and since they have potential for serious toxic effects in humans. Research will be directed towards characterizing those factors which affect the mammalian biotransformation reactions of organophosphorus insecticides, as well as the consequences of such reactions. It is expected that these studies will provide information useful in assessing the health hazards of organophosphorus insecticides, as well as their potential for toxic interactions with certain other foreign chemicals. Additionally this proposed research will contribute to the fundamental knowledge of those metabolic systems involved in the biotransformation of these insecticides. The specific aims in this research are as follows: 1) To continue to investigate the toxicological significance of extrahepatic activation of certain organothiophosphorus insecticides. 2) To investigate why glutathione-dependent detoxification of numerous dimethyl-substituted organophosphorus insecticides occurs in vitro but not in vivo. 3) To identify and characterize factors which affect hepatic and serum A-esterase activities. Included in this aim will be the investigation of kinetic and physiochemical differences between "high activity" and "low activity" forms of human serum A-esterase. 4) To characterize biochemically the two forms of A-esterase purified from mouse hepatic microsomes in this laboratory. 5) To characterize the factors affecting secretion of A-esterase(s) from liver. These studies will also focus on comparisons of the secreted form(s) of A-esterase(s) with those forms found in hepatic microsomes.